Size-selective hemocompatible polymer system

ABSTRACT

A size-selective hemocompatible porous polymeric adsorbent system is provided, the polymer system comprises at least one crosslinking agent and at least one dispersing agent, and the polymer has a plurality of pores with diameters in the range from about 17 to about 40,000 Angstroms.

RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.12/807,597 filed on Sep. 9, 2010 now U.S. Pat. No. 8,211,310 entitled“Size Selective Polymer System”, which is a continuation-in-part of U.S.application Ser. No. 11/601,931 filed on Nov. 20, 2006 now U.S. Pat. No.7,875,182 entitled “Size Selective Hemoperfusion Polymeric Adsorbents”.

BACKGROUND OF INVENTION

Field of Invention

The present invention relates to size selective hemocompatible polymersystem and in particular, polymer systems having a plurality of poreswith transport pores and a negative ionic charge on its surface.

The size-selective porous polymeric adsorbents of this invention arebiocompatible and hemocompatible and are designed to function in directcontact with body fluids. These adsorbents are useful in conjunctionwith hemodialysis for extracting and controlling the blood level ofβ₂-microglobulin without significantly perturbing the levels of albumin,immunoglobulins, leukocytes, erythrocytes, and platelets. Thesepolymeric adsorbents are also very effective in extracting cytokinesassociated with the systemic inflammatory response syndrome (SIRS), fromthe blood and/or physiologic fluid, in patients with sepsis, burns,trauma, influenza, etc. while keeping the physiologically requiredcomponents of blood at clinically acceptable levels.

Description of Related Art

Techniques of extracorporeal blood purification are important in manymedical treatments including hemodialysis, hemofiltration,hemoperfusion, plasma perfusion and combinations of these methods.Hemodialysis and hemofiltration involve passing whole blood throughhollow fibers to remove excess water and compounds of small molecularsize but are unable to remove protein toxins such asbeta-2-microglobulin (B2M) and the cytokines. Hemoperfusion is passingwhole blood over an adsorbent to remove contaminants from the blood.Plasma perfusion is passing blood plasma through an adsorbent. Inhemoperfusion, the treated whole blood returns to the patient's bloodcirculation system.

In addition to the common requirements such as hemocompatibility andsterility for medical devices, an ideal adsorbent for hemoperfusion andplasma perfusion should have an adsorption capacity and selectivityadequate for adsorbing toxins to the exclusion of useful components inorder to be beneficial to the patient.

Conventional adsorbing materials include activated carbon, silicates,diatomite and synthetic porous resins. Activated carbon has beenreported in extracorporeal adsorption for treating schizophrenia(Kinney, U.S. Pat. No. 4,300,551; 1981). Various synthetic polymericadsorbents have been disclosed for removing toxic shock syndrometoxin-1, bradykinin and endotoxin from blood (Hirai, et al. U.S. Pat.Nos. 6,315,907; 2001; 6,387,362; 2002, and 6132610; 2000), and forremoving poisons and/or drugs from the blood of animals (Kunin, et al.,U.S. Pat. No. 3,794,584; 1974). Adsorption by the above adsorbents isgenerally rather nonselective and, therefore, is limited to short termtreatments.

Most commercial porous resins are synthesized either by macroreticularsynthesis (Meitzner, et al., U.S. Pat. No. 4,224,415; 1980), such asAmberlite XAD-4® and Amberlite XAD-16® by Rohm and Haas Company or byhypercrosslinking synthesis [Davankov, et al. J. Polymer Science,Symposium No. 47, 95-101 (1974)], used to make the Hpersol-Macronet®resins by Purolite Corp. Many conventional polymeric adsorbents have alarge pore surface and adsorption capacity but a lack of selectivity dueto the broad distribution of pore sizes. Others are produced to adsorbsmall organic molecules or are not hemocompatible and therefore are notsuitable for selective adsorption of midsize proteins directly from bodyfluids.

In order to enhance the hemocompatibility, many techniques involvecoating the hydrophobic adsorbent with hydrophilic materials such aspolyacrylamide and poly(hydroxyethylmethacrylate) (Clark, U.S. Pat. No.4,048,064; 1977; Nakashima, et al., U.S. Pat. No. 4,171,283; 1979). Acopolymer coating of 2-hydroxyethyl methacrylate with diethylaminoethylmethacrylate is reported by Watanabe, et al. (U.S. Pat. No. 5,051,185;1991). Davankov, et al. (U.S. Pat. No. 6,114,466; 2000) disclosed amethod of grafting to the external surface of porous polymeric beadshydrophilic monomers including 2-hydroxyethyl methacrylate,N-vinylpyrrolidinone, N-vinylcaprolactam and acrylamide. Recently,Albright (U.S. Pat. No. 6,884,829 B2; 2005) disclosed the use of surfaceactive dispersants [including polyvinyl alcohol, poly(dimethylaminoethylmethacrylate), poly(vinylpyrrolidinone), and hydroxethylcellulose]during macroreticular synthesis to yield a hemocompatible surface onporous beads in a one step synthesis.

The internal pore structure (distribution of pore diameters, porevolume, and pore surface) of the adsorbent is very important toadsorption selectivity. A cartridge containing a packed bed of adsorbentwith effective pore diameters ranging from 2 Å to 60 Å (Angstrom) wasdisclosed for hemoperfusion by Clark (U.S. Pat. No. 4,048,064; 1977).This pore size range was primarily specified for detoxification andpreventing adsorption of anticoagulants, platelets and leukocytes fromthe blood but is inadequate for adsorbing midsize proteins such ascytochrome-c and beta-2-microglobulin. Similarly, coating inorganicadsorbents, such as silicate and diatomite, with a membrane film havingpore sizes greater than 20 Å was disclosed by Mazid (U.S. Pat. No.5,149,425; 1992) for preparing hemoperfusion adsorbents. More recently,Giebelhausen (U.S. Pat. No. 551,700; 2003) disclosed a sphericaladsorbent with pronounced microstructure with 0-40 Å pore diameters andan overall micropore volume of at least 0.6 cm³/g for adsorption ofchemical warfare agents, toxic gases and vapors, and refrigeratingagents. The above pore structures are too small for adsorption ofmidsize proteins from physiologic fluids.

An adsorbent with a broad distribution of pore sizes (40˜9,000 Ådiameter) was disclosed for adsorbing proteins, enzymes, antigens, andantibodies by Miyake et al. (U.S. Pat. No. 4,246,351; 1981). Theadsorbent sorbs both the toxins as well as the beneficial proteins suchas albumin from the blood due to its broad pore size distribution.Immobilizing antibodies and IgG-binding proteins onto porous polymericadsorbents were described to enhance selectivity of adsorbents havingbroad pore size distributions for lowering low density lipoproteins, fortreating atherosclerosis, for adsorbing rheumatoid arthritis factor(Strahilevitz, U.S. Pat. No. 6,676,622; 2004), and for removinghepatitis C virus from blood (Ogino et al. U.S. Pat. No. 6,600,014;2003). The antibodies or proteins bound to adsorbents, however, couldgreatly increase the side effects for a hemoperfusion or a plasmaperfusion device and could greatly increase the difficulty formaintaining sterility of the devices.

Removal of beta-2-microglobulin by direct hemoperfusion was beneficialto renal patients (Kazama, “Nephrol. Dial. Transplant”, 2001, 16:31-35).An adsorbent with an enhanced portion of pores in a diameter rangebetween 10 and 100 Å was described by Braverman et al. (U.S. Pat. No.5,904,663; 1999) for removing beta-2-microglobulin from blood and byDavankov et al (U.S. Pat. No. 6,527,735; 2003) for removing toxins inthe molecular weight range of 300-30,000 daltons from a physiologicfluid. Strom, et al. (U.S. Pat. No. 6,338,801; 2002) described asynthesis method for polymer resins with pore sizes in the range from 20Å to 500 Å intended for adsorbing beta-2-microglobulin. The in-vitrostudy by the present inventors shows that the pore structures proposedby Davankov and Strom, however, are inadequate for a selectiveadsorption of midsize proteins such as beta-2-microglobulin andcytochrome-c in the presence of serum albumin.

In contrast to prior disclosures, the porous polymeric adsorbentsspecified in the present invention demonstrate a high selectivity foradsorbing small and midsize proteins to the exclusion of the largeproteins with molecular weights greater than 50,000 daltons. Moresignificantly, the present invention discloses adsorbents forhemoperfusion suitable for long term clinical treatment, since thehealthy components such as albumin, red blood cells, platelets and whiteblood cells are maintained at clinically acceptable levels.

SUMMARY OF INVENTION

In one embodiment, the present invention provides for a polymer systemcomprising at least one polymer with a plurality of pores, and thepolymer has at least one transport pore with a diameter from about 250Angstroms to about 2000 Angstroms, and the polymer has a transport porevolume greater than about 1.8% to about 78% of a capacity pore of volumeof the polymer.

For purposes of this invention, the term “transport pore” is defined asa pore that allows for a fast “transport” of the molecules to theeffective pores and the term “transport pore volume” means the volume ofthe “transport” pores per unit mass of the polymer.

In another embodiment, the pores have diameters from greater than 100Angstrom to about 2000 Angstrom. In yet another embodiment, the polymeris capable of sorbing protein molecules greater than 20,000 to less than50,000 Daltons from blood and excluding the sorption of blood proteinsgreater than 50,000 Daltons.

In still another embodiment, the polymer has a pore volume from about0.315 cc/g to about 1.516 cc/g. In still yet another embodiment, thepolymer has effective pore volume greater than from about 21.97% toabout 98.16% of the capacity pore volume. In a further embodiment, thepolymer comprises effective pores, said effective pores having adiameter from greater than about 100 Angstroms to about 250 Angstroms.

For purposes of this invention, the term “total pore volume” is definedas the volume of all the pores in a polymer per unit mass and the term“effective pore volume” means any pore which is selective adsorption ofmolecules. The term “capacity pore volume” is defined as the volume ofthe “capacity” of all the pores per unit mass of polymer and the term“effective pores” means the functional pores designed to adsorbparticular molecules. The term “capacity pore” is the total sum of theeffective pores and transport pores.

In another further embodiment, the polymer is biocompatible. In yetanother embodiment, the polymer is hemocompatible. In still a furtherembodiment, the geometry of the polymer is a spherical bead.

In yet a further embodiment, the polymer is used in direct contact withwhole blood to sorb protein molecules selected from a group consistingessentially of cytokines and β₂-microglobulin and exclude the sorptionof large blood proteins, and the large blood proteins are selected froma group consisting essentially of hemoglobin, albumin, immunoglobulins,fibrinogen, serum proteins and other blood proteins larger than 50,000Daltons.

In still yet a further embodiment, the polymer has an internal surfaceselectivity for adsorbing proteins smaller than 50,000 Daltons, havinglittle to no selectivity for adsorbing vitamins, glucose, electrolytes,fats, and other hydrophilic small molecular nutrients carried by theblood.

In another embodiment, the polymer is made using suspensionpolymerization. In still another embodiment, the polymer is constructedfrom aromatic monomers of styrene and ethylvinylbenzene with acrosslinking agent selected from a group consisting essentially ofdivinylbenzene, trivinylcyclohexane, trivinylbenzene,divinylnaphthalene, divinylsulfone, trimethylolpropane triacrylate,trimethylolpropane trimethacrylate and mixtures thereof.

In another embodiment, the crosslinking agent is DVD in amount fromabout 20% to about 90% of the polymer.

In yet another embodiment, the stabilizing agent for the dropletsuspension polymerization is selected from a group consistingessentially of hemocompatibilizing polymers, said polymers beingpoly(N-vinylpyrrolidinone), poly(hydroxyethyl acrylate),poly(hydroxyethyl methacrylate), hydroxylethyl cellulose, hydroxypropylcellulose, salts of poly(acrylic acid), salts of poly(methacrylic acid),poly(dimethylaminoethyl acrylate), poly(dimethylaminoethylmethacrylate), poly(diethylaminoethyl acrylate), poly(diethylaminoethylmethacrylate), poly(vinyl alcohol) and mixtures thereof.

In still yet another embodiment, the polymer is made hemocompatible byexterior coatings selected from a group consisting essentially ofpoly(N-vinylpyrrolidinone), poly(hydroxyethyl acrylate),poly(hydroxyethyl methacrylate), hydroxyethyl cellulose, hydroxypropylcellulose, salts of poy(acrylic acid), salts of poly(methacrylic acid),poly(dimethylaminoethyl methacrylate), poly(dimethylaminoethylacrylate), poly(diethylaminoethyl acrylate), poly(diethylaminoethylmethacrylate), poly(vinyl alcohol) and mixtures thereof.

In a further embodiment, the polymer is made hemocompatible by surfacegrafting of the hemocompatible exterior coatings concomitantly withformation of the porous polymer beads.

In another further embodiment, the polymer is made hemocompatible bysurface grafting of the hemocompatible exterior coatings onto thepreformed porous polymeric beads.

In still another further embodiment, the polymer has an external surfacewith a negative ionic charge, and the negative ionic charge preventsalbumin from entering said pores.

In yet another further embodiment, the present invention relates to asize selective polymer comprising at least one polymer with a pluralityof pores, and the pores have diameters from greater than 100 Angstrom toabout 2000 Angstrom, and the polymer has a transport pore volume greaterthan about 1.8% to about 78% of a capacity pore of volume of thepolymer.

In still yet another further embodiment, the present invention providesfor a size selective polymer comprising a plurality of pores, and thepores have diameters from greater than 100 Angstrom to about 2000Angstrom, and the polymer has at least one transport pore with adiameter from about 250 Angstroms to about 2000 Angstroms, and thepolymer has an external surface with a negative ionic charge, and thenegative ionic charge prevents albumin from entering said pores at a pHfrom about 7.2 to about 7.6.

In one embodiment, the present invention relates to a porous polymer forsorbing small to midsize protein molecules and excluding sorption oflarge blood proteins, the polymer comprising a plurality of pores. Thepores sorb small to midsize protein molecules equal to or less than50,000 Daltons. In another embodiment, the polymer is biocompatibleand/or hemocompatible.

In yet another embodiment, the polymer comprises a plurality of poreswith diameters from about 75 Angstrom to about 300 Angstrom. In anotherembodiment, the polymer can have a plurality of pores within the aboverange. In another further embodiment, the polymer has its working poreswithin the above mentioned range and can also have non-working poresbelow the 75 Angstrom range. In another embodiment, the polymer has nomore than 2.0 volume % of its total pore volume in pores with diametersgreater than 300 Angstroms. For purposes of this invention, the term“large blood proteins” is defined as any blood protein greater than50,000 Daltons in size and the term “blood protein molecules” relates tosmall to midsize blood proteins equal to or less than 50,000 Daltons.

In still yet another embodiment, the geometry of the polymer is aspherical bead. In a further embodiment, the polymer has a pore volumegreater than 98.0% in pores smaller than 300 Angstroms diameter.

In another further embodiment, the polymer is used in direct contactwith whole blood to adsorb protein molecules such as β₂-microglobulinbut excluding the sorption of larger blood proteins, said large bloodproteins being selected from a group consisting essentially ofhemoglobin, albumin, immunoglobulins, fibrinogen, serum proteins largerthan 50,000 Daltons and mixtures thereof. In yet another furtherembodiment, the polymer has an internal surface selectivity foradsorbing proteins smaller than 50,000 Daltons, having little to noselectivity for adsorbing vitamins, glucose, electrolytes, fats, andother hydrophilic small molecular nutrients carried by the blood.

In still a further embodiment, the polymer is made porous usingmacroreticular synthesis or macronet synthesis. In still yet a furtherembodiment, the polymer is made using suspension polymerization.

In another embodiment, the polymer is constructed from aromatic monomersof styrene and ethylvinylbenzene with crosslinking provided bydivinylbenzene, trivinylcyclohexane, trivinylbenzene,divinylnaphthalene, divinylsulfone, trimethylolpropane triacrylate,trimethylolpropane trimethacrylate and mixtures thereof.

In yet another embodiment, the stabilizing agent for the dropletsuspension polymerization is selected from a group consistingessentially of hemocompatibilizing polymers, said polymers beingpoly(N-vinylpyrrolidinone), poly(hydroxyethyl acrylate),poly(hydroxyethyl methacrylate), hydroxylethyl cellulose, hydroxypropylcellulose, salts of poly(acrylic acid), salts of poly(methacrylic acid),poly(dimethylaminoethyl acrylate), poly(dimethylaminoethylmethacrylate), poly(diethylaminoethyl acrylate), poly(diethylaminoethylmethacrylate), poly(vinyl alcohol) and mixtures thereof.

In still another embodiment, the polymer is made hemocompatible byexterior coatings of poly(N-vinylpyrrolidinone), poly(hydroxyethylacrylate), poly(hydroxyethyl methacrylate), hydroxyethyl cellulose,hydroxypropyl cellulose, salts of poy(acrylic acid), salts ofpoly(methacrylic acid), poly(dimethylaminoethyl methacrylate),poly(dimethylaminoethyl acrylate), poly(diethylaminoethyl acrylate),poly(diethylaminoethyl methacrylate), poly(vinyl alcohol) and mixturesthereof.

In yet another embodiment, the polymer is made hemocompatible by surfacegrafting of the hemocompatible exterior coatings concomitantly withformation of the porous polymer beads. In still yet another embodiment,the polymer is made hemocompatible by surface grafting of thehemocompatible exterior coatings onto the preformed porous polymericbeads.

In a further embodiment, the present invention relates to a polymerabsorbent for excluding albumin from sorption. The polymer comprisespores with diameters from about 75 Angstrom to about 300 Angstrom.

In another further embodiment, the present invention provides ahemocompatible polymer comprising a working pore range. The working porerange has pore diameters from about 75 Angstrom to about 300 Angstromand the polymer is designed to adsorb blood protein molecules.

In another embodiment, the present invention relates to a size selectivepolymer for sorbing small to midsize blood borne proteins and excludingthe sorption of large blood borne proteins; the polymer comprises aplurality of pores, and the pores have diameters from about 75 Angstromto about 300 Angstrom. The polymer is used in direct contact with wholeblood to adsorb cytokines and β₂-microglobulin but excludes theadsorption of large blood borne proteins, and the large blood borneproteins are selected from a group consisting essentially of hemoglobin,albumin, immunoglobulins, fibrinogen, serum proteins larger than 50,000Daltons and mixtures thereof. For purposes of this invention, the term“blood borne proteins” includes enzymes, hormones and regulatoryproteins such as cytokines and chemokines.

The present invention discloses size-selective, biocompatible, andhemocompatible porous polymeric adsorbents whose pore structures aredesigned for efficacy in hemoperfusion. For efficacy in hemoperfusion,the adsorbents must sorb proteins selectively over the other smallmolecular species and the hydrophilic molecules present in blood. Theprotein sorption must also be restricted to molecular sizes smaller than50,000 daltons so that the important proteins required for healthhomeostasis-albumin, immunoglobulins, fibrinogen-remain in the bloodduring the hemoperfusion treatment.

The porous polymeric adsorbents of this invention have a hemocompatibleexterior surface coating and an internal pore system with an aromaticpore surface for protein selectivity and a major pore volume fallingwithin the pore diameter range of 100 to 300 Å with essentially no poreslarger than 300 Å in diameter. The pore volume in pores larger than 300Å is 2.0% or less of the total pore volume. These porous polymericadsorbents exclude entrance into the pore system of protein moleculeslarger than 50,000 Daltons but provide good mass transport into the poresystem for the protein molecules with sizes smaller than 35,000 Daltons.

The porous polymers of this invention are constructed from aromaticmonomers of styrene and ethylvinylbenzene with crosslinking provided byone of the following or mixtures of the following of divinylbenzene,trivinylcyclohexane, trimethylolpropane triacrylate andtrimethylolpropane trimethacrylate. Other crosslinking agents that maybe used to construct the porous polymeric adsorbents of this inventionare divinylnaphthalene, trivinylbenzene and divinylsulfone and mixturesthereof.

In another embodiment, the polymer adsorber is synthesized by an organicsolution in which 25 mole % to 90 mole % of the monomer is crosslinkingagents such as divinylbenzene and trivinylbenzene, and the resultingpolymer adsorber has a sufficient structural strength.

The porous polymers of this invention are made by suspensionpolymerization in a formulated aqueous phase with free radicalinitiation in the presence of aqueous phase dispersants that areselected to provide a biocompatible and a hemocompatible exteriorsurface to the formed polymer beads. The beads are made porous by themacroreticular synthesis with an appropriately selected porogen(precipitant) and an appropriate time-temperature profile for thepolymerization in order to develop the proper pore structure.

Porous beads are also made with small pore sizes by thehypercrosslinking methodology which is also known as macronetting or themacronet synthesis. In this methodology, a lightly crosslinked gelpolymer—crosslinking usually less than two (2) wt. %—is swelled in agood difunctional swelling agent for the polymeric matrix. In theswollen state, the polymeric matrix is crosslinked by a catalyzedreaction. The catalyzed reaction is most often a Friedel-Crafts reactioncatalyzed by a Lewis-acid catalyst. The resulting product is amacroporous polymer which is a crosslinked polymer having a permanentpore structure in a dry, non-swollen state.

For the purposes of this invention, the term “biocompatible” is definedas a condition of compatibility with physiologic fluids withoutproducing unacceptable clinical changes within the physiologic fluids.The term “hemocompatible” is defined as a condition whereby a materialwhen placed in contact with whole blood or blood plasma results inclinically acceptable physiologic changes.

The biocompatible and hemocompatible exterior surface coatings on thepolymer beads are covalently bound to the bead surface by free-radicalgrafting. The free-radical grafting occurs during the transformation ofthe monomer droplets into polymer beads. The dispersant coating andstabilizing the monomer droplets becomes covalently bound to the dropletsurface as the monomers within the droplets polymerize and are convertedinto polymer. Biocompatible and hemocompatible exterior surface coatingscan be covalently grafted onto the preformed polymer beads if thedispersant used in the suspension polymerization is not one that impartsbiocompatibility or hemocompatibility. Grafting of biocompatible andhemocompatible coatings onto preformed polymer beads is carried out byactivating free-radical initiators in the presence of either themonomers or low molecular weight oligomers of the polymers that impartbiocompatibility or hemocompatibility to the surface coating.

Biocompatible and hemocompatible exterior surface coatings on polymerbeads are provided by a group of polymers consisting ofpoly(N-vinylpyrrolidinone), poly(hydroxyethyl methacrylate),poly(hydroxyethyl acrylate), hydroxyethyl cellulose, hydroxypropylcellulose, salts of poly(acrylic acid), salts of poly(methacrylic acid),poly(dimethylaminoethyl methacrylate), poly(dimethylamnoethyl acrylate),poly(diethylaminoethyl acrylate), poly(diethylaminoethyl methacrylate),and poly(vinyl alcohol).

In one embodiment, the exterior surface coatings such aspoly(methacrylate) and poly(acrylate) polymers form anionic ions at pH7.2 to 7.6 and the said exterior surface expel albumin which carries anet negative ionic charge at normal blood pH (7.4) and inhibiting thealbumin from entering the pores at the exterior surface of the absorberby repulsion. In yet another embodiment, the thin layer external surfaceof the divinylbenzene copolymer is modified to become an anionicexchanger so that the external surface forms negative charges to expelthe albumin from entering the inner pores of the adsorber. Albumin hasan isoelectric point at pH 4.6 and has a net negative charge in normalpH of blood and other physiological fluid. With the negative charges onthe thin layer of the external surface of the adsorber, the pore sizelimitation can be expanded to a wider range while the said polymer stillexhibit a selectivity preference of adsorbing toxin to albumin.

The hemoperfusion and perfusion devices consist of a packed bead bed ofthe size-selective porous polymer beads in a flow-through containerfitted with a retainer screen at both the exit end and the entrance endto keep the bead bed within the container. The hemoperfusion andperfusion operations are performed by passing the whole blood, bloodplasma or physiologic fluid through the packed bead bed. During theperfusion through the bead bed, the protein molecules smaller than35,000 Daltons are extracted by adsorption while the remainder of thefluid components pass through essentially unchanged in concentration.

For the purposes of this invention, the term “perfusion” is defined aspassing a physiologic fluid by way of a suitable extracorporeal circuitthrough a device containing the porous polymeric adsorbent to removetoxins and proteins from the fluid. The term “hemoperfusion” is aspecial case of perfusion where the physiologic fluid is blood. The term“dispersant” or “dispersing agent” is defined as a substance thatimparts a stabilizing effect upon a finely divided array of immiscibleliquid droplets suspended in a fluidizing medium. The term“macroreticular synthesis” is defined as a polymerization of monomersinto polymer in the presence of an inert precipitant which forces thegrowing polymer molecules out of the monomer liquid at a certainmolecular size dictated by the phase equilibria to give solid nanosizedmicrogel particles of spherical or almost spherical symmetry packedtogether to give a bead with physical pores of an open cell structure[U.S. Pat. No. 4,297,220, Meitzner and Oline, Oct. 27, 1981; R. L.Albright, Reactive Polymers, 4, 155-174 (1986)]. For purposes of thisinvention, the term “sorb” is defined as “taking up and binding byabsorption and adsorption”.

In one embodiment, the present invention relates to a hemocompatabe sizeselective polymer comprising at least one crosslinking agent and atleast one dispersing agent, and the polymer has a plurality of poreswith diameters in the range from about 17 to about 40,000 Angstroms.

In another embodiment, the crosslinking agent is selected from a groupconsisting of divinylbenzene, trivinylbenzene, divinylnaphthalene,trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate,trimethylolpropane dimethacrylate, trimethylolpropane triacrylate,trimethylolpropane diacrylate, pentaerythrital dimethacrylates,pentaerythrital trimethacrylates, pentaerythrital, tetramethacrylates,pentaerythritol diacrylates, pentaerythritol triiacrylates,pentaerythritol tetraacrylates, dipentaerythritol dimethacrylates,dipentaerythritol trimethacrylates, dipentaerythritoltetramethacrylates, dipentaerythritol diacrylates, dipentaerythritoltriacrylates, dipentaerythritol tetraacrylates, divinylformamide andmixtures thereof.

In yet another embodiment, the dispersing agent is selected from a groupconsisting of albumin, carrageenan, konjac flour (glucomannan), guar gum(galactomannan), xanthan gum (polysaccharide of mannose, glucose, andglucuronic acid), gum arabic, gum tragacanth, locust bean gum, karayagum, salts of carboxymethylcellulose, salts of carboxyethylcellulose,salts of hyaluronic acid, salts of poly(maleic acid), salts ofpoly(maleic acid-co-acrylic acid), salts of poly(maleicacid-co-methacrylic acid), salts of poly(itaconic acid), Type B gelatin,poly(acrylamide), poly(methacrylamide), salts ofpoly(acrylamide-co-acrylic acid), salts ofpoly(acrylamide-co-methacrylic acid), salts ofpoly(methacrylamide-co-acrylic acid), salts ofpoly(methacrylamide-co-methacrylic acid), hydroxyethyl cellulose,hydroxypopyl cellulose, poly(hydroxyethyl methacrylate),poly(hydroxyethyl acrylate), poly(hydroxypropyl methacrylate),poly(hydroxypropyl acrylate), poly(dimethylaminoethyl methacrylate),poly(dimethylaminoethyl acrylate), poly(diethylamimoethyl methacrylate),poly(diethylaminoethyl acrylate), poly(vinyl alcohol),poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and saltsof poly(acrylic acid) and mixtures thereof. In still another embodiment,the dispersing agent forms a hemocompatible surface on the polymer. Instill yet another embodiment, the pores have diameters in the range fromabout 17 to about 2000 Angstroms.

In a further embodiment, the polymer further comprises effective pores,and the effective pores have a diameter from greater than about 250Angstroms to about 250 Angstroms, the polymer has an effective porevolume greater than from about 21.97% to about 98.16% of the capacitypore volume.

In yet a further embodiment, the polymer further comprises transportpores, and the effective pores have a diameter from greater than about100 Angstroms to about 250 Angstroms, and the polymer has a transportpore volume greater than about 1.8% to about 78% of a capacity porevolume of said polymer.

In another embodiment, the polymer is used in direct contact with wholeblood to sorb protein molecules selected from a group consistingessentially of cytokines and β₂-microglobulin and exclude the sorptionof large blood proteins, said large blood proteins being selected from agroup consisting essentially of hemoglobin, albumin, immunoglobulins,fibrinogen, serum proteins and other blood proteins larger than 50,000Daltons.

In yet another embodiment, the polymer has an internal surfaceselectivity for adsorbing proteins smaller than 50,000 Daltons, havinglittle to no selectivity for adsorbing vitamins, glucose, electrolytes,fats, and other hydrophilic small molecular nutrients carried by theblood.

In still another embodiment, the polymer is made using suspensionpolymerization.

In still yet another embodiment, the present invention provides for asize selective hemocompatible surface coated polymer system comprisingan organic phase and an aqueous phase, and the organic phase comprisespolymerizable monomers and at least one initiator and the aqueous phasecomprises at least one dispersing agent, at least one free radicalinhibitor and at least one buffering agent, said organic phase beingimmiscible in said aqueous phase, wherein the organic phase forms apolymer, and the polymer having a plurality of pores with diameters inthe range from about 17 to about 40,000 Angstroms.

In another embodiment, the monomers are monofunctional monomers, and themonofunctional monomers are selected from a group consisting of styrene,ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate,butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate,ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene,vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methylacrylate and mixtures thereof.

In a further embodiment, the monomers are polyfunctional monomers, andthe polyfunctional monomers are selected from a group consisting ofdivinylbenzene, trivinylbenzene, divinylnaphthalene,trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate,trimethylolpropane dimethacrylate, trimethylolpropane triacrylate,trimethylolpropane diacrylate, pentaerythritol dimethacrylate,pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate,pentaerythritol diacrylate, pentaerythritol triiacrylate,pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate,dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate,dipentaerythritol diacrylate, dipentaerythritol triacrylate,dipentaerythritol tetraacrylate, divinylformamide and mixtures thereof.

In yet a further embodiment, the initiator is selected from a groupconsisting of diacyl peroxides, ketone peroxides, peroxyesters, dialkylperoxides, peroxyketals, azoalkylnitriles, peroxydicarbonates andmixtures thereof.

In still a further embodiment, the dispersing agent is selected from agroup consisting of albumin, carrageenan, konjac flour (glucomannan),guar gum (galactomannan), xanthan gum (polysaccharide of mannose,glucose, and glucuronic acid), gum arabic, gum tragacanth, locust beangum, karaya gum, salts of carboxymethylcellulose, salts ofcarboxyethylcellulose, salts of hyaluronic acid, salts of poly(maleicacid), salts of poly(maleic acid-co-acrylic acid), salts of poly(maleicacid-co-methacrylic acid), salts of poly(itaconic acid), Type B gelatin,poly(acrylamide), poly(methacrylamide), salts ofpoly(acrylamide-co-acrylic acid), salts ofpoly(acrylamide-co-methacrylic acid), salts ofpoly(methacrylamide-co-acrylic acid), salts ofpoly(methacrylamide-co-methacrylic acid), hydroxyethyl cellulose,hydroxypopyl cellulose, poly(hydroxyethyl methacrylate),poly(hydroxyethyl acrylate), poly(hydroxypropyl methacrylate),poly(hydroxypropyl acrylate), poly(dimethylaminoethyl methacrylate),poly(dimethylaminoethyl acrylate), poly(diethylamimoethyl methacrylate),poly(diethylaminoethyl acrylate), poly(vinyl alcohol),poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and saltsof poly(acrylic acid) and mixtures thereof.

In still yet a further embodiment, the free radical inhibitor isselected from a group consisting of p-nitrosophenoxide salts, sodiumnitrate, N-hydroxy-N-methylglucamine, N-nitroso-N-methylglucamine andmixtures thereof.

In another embodiment, the buffering agent is selected from a groupconsisting of carbonate salts, bicarbonate salts, boric acid salts,salts of phosphoric acid and mixtures thereof.

In a further embodiment, the organic phase further comprises at leastone porogen, said porogen being selected from a group consisting ofaliphatic hydrocarbons, dialkyl ketones, aliphatic carbinols andmixtures thereof.

In another further embodiment, the present invention relates to a methodof manufacturing a size selective biocompatible coated polymer, and themethod comprises: polymerizing monomer droplets comprising at least onecross agent to form a polymer and simultaneously coating the resultantpolymer using a least one polymeric dispersing agent to thereby form abiocompatible coated polymer; and forming a plurality of pores withdiameters in the range from about 17 to about 40,000 Angstroms.

In still another further embodiment, the present invention relates to ahemocompatible surface coated polymer system comprising an organic phaseand an aqueous phase, the system being manufactured by a methodcomprising: forming the organic phase comprising polymerizable monomersand at least one initiator; forming the aqueous phase comprising atleast one dispersant agent, at least one free radical inhibitor, and atleast one buffering agent; dispersing the organic phase into the aqueousphase to thereby form organic phase droplets; and polymerizing theorganic phase droplets coated with the dispersing agent to thereby formthe hemocompatible surface coating on the polymer. In yet anotherfurther embodiment, the polymerization of the organic phase is formed byheating a mixture of the organic and aqueous phases.

For purposes of this invention, the term “hemocompatibility” is definedas a condition whereby a material, when placed in contact with wholeblood and blood components or physiological fluids, results inclinically acceptable physiological changes. In another embodiment, thedispersing agent is a biocompatibilizing polymer. A “biocompatibilizingpolymer” is defined as a polymer, which forms a surface over anon-biocompatible material, making the polymeric system compatible withphysiological fluids and tissues. The term “crosslinking agent” isdefined as a linking agent such as a polyfunctional monomer that linkstwo or more polymer chains or segments of the same polymer chaintogether. The term “dispersing agent” is defined as a substance thatimparts a stabilizing effect upon a finely divided array of immiscibleparticles suspended in a fluidizing medium. The immiscible particles canbe a solid, liquid or gas and the fluidizing medium can be a liquid or agas.

In still a further embodiment, the polymer is processed in non-pyrogenicwater. For purposes of this invention, “non-pyrogenic” shall be definedby U.S.P. 25, Monograph (151) Pyrogenic Test, U.S. Pharmacopeia NationalFormulary.

In still yet another embodiment, the polymer of the present invention isprepared by suspension polymerization. For purposes of the invention,suspension polymerization is defined as the polymerization of monomerdroplets dispersed in an immiscible liquid. Based upon an ElementalAnalysis of the Polymer's Surface by X-Ray Photoelectron Spectroscopy(XPS), the dispersing agent becomes chemically grafting onto the surfaceof the polymer as the monomer droplets are transformed into polymericbeads. Polymers coated with poly(N-vinylpyrrolidinone) have been foundto be biocompatible and hemocompatible. The hemocompatible polymers ofthe present invention pass the Lee White clotting tests and the testsfor the hemolysis of red blood cells.

In another embodiment, the polymer of the present invention is a porouspolymer. The term “porous polymer” is defined as a polymer particlehaving an internal pore structure with a porosity resulting from voidsor holes throughout the polymer matrix. In still another embodiment, thepolymer is an ion exchange resin or polymer. An ion exchange resin orpolymer is a resin or polymer carrying ionogenic groups that are capableof exchanging ions or of sequestering ions. The ion exchange polymers ofthe present invention are beneficial when used with blood for removingand isolating varying ions and ionogenic molecules.

In another embodiment, the present invention relates to a method ofmanufacturing a biocompatible and hemocompatible surface coated polymer.In still another embodiment, the method comprises: polymerizing monomerdroplets comprising at least one crosslinking agent and simultaneouslycoating the resulting polymer beads using at least one dispersing agentto form a biocompatible surface coated polymer. In still anotherembodiment, the coated polymers are hemocompatible. In yet anotherembodiment, the polymer is formed using a suspension polymerizationprocedure. In another embodiment, the polymer is formed using anemulsion polymerization procedure followed by growing the particles withadditional monomer feed.

In still another embodiment, the present invention relates to anapplication of use whereby the hemocompatible surface coated polymers ofthe present invention are utilized for medical applications. In anotherembodiment, the hemocompatible polymers of the present invention may beused to isolate and/or remove target substances from blood andphysiological fluids and for specific treatments. In a furtherembodiment, the hemocompatible polymers of the present invention may beused in preserving organs. In yet another embodiment, the presentinvention relates to an apparatus for isolating blood components and forpurifying blood using the hemocompatible surface coated polymers of thepresent invention. In one embodiment, the apparatus comprises acartridge containing the hemocompatible polymers of the presentinvention.

In still yet a further embodiment, the present invention also relates toa method of manufacturing a hemocompatible surface coated polymer usinga one step process, the method comprising: polymerizing monomer dropletscomprising at least one crosslinking agent to form a polymer anddeveloping a surface coating on the polymer by using at least onedispersing agent carrying hydroxyl groups followed by a reaction ofhydroxyl groups with a vinyl monomer or polymer to thereby form thehemocompatible surface coating on the polymer.

In another embodiment, the present invention relates to a polymer havinga hemocompatible-coated surface, the polymer being manufactured by atwo-step process comprising: polymerizing monomer droplets comprising atleast one crosslinking agent and at least one dispersing agent to form apolymer; and coating the surface of the polymer by crosslinking amonovinyl monomer and a polyfunctional monomer mixture over the surfaceof the polymer bead to thereby form the hemocompatible coating on thesurface of the polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a furtherunderstanding of the present invention. These drawings are incorporatedin and constitute a part of this specification, illustrate one or moreembodiments of the present invention and together with the description,serve to explain the principles of the present invention.

FIG. 1 is a graph of Table 2 showing a plot of pore volume v porediameter (dV/dD vs. D) for Various Adsorbents Measured by NitrogenDesorption Isotherm.

Among those benefits and improvements that have been disclosed, otherobjects and advantages of this invention will become apparent from thefollowing description taken in conjunction with the accompanyingdrawings. The drawings constitute a part of this specification andinclude exemplary embodiments of the present invention and illustratevarious objects and features thereof.

DETAILED DESCRIPTION OF THE INVENTION

As required, detailed embodiments of the present invention are disclosedherein; it is to be understood that the disclosed embodiments are merelyexemplary of the invention that may be embodied in various forms.Therefore, specific structural and functional details disclosed hereinare not to be interpreted as limits, but merely as a basis for teachingone skilled in the art to employ the present invention. The specificexamples below will enable the invention to be better understood.However, they are given merely by way of guidance and do not imply anylimitation.

Five porous polymeric adsorbents are characterized for their porestructures and are assessed for their competitive adsorption ofcytochrome-c (11,685 Daltons in size) over serum albumin (66,462 Daltonsin size). The adsorbent syntheses are described in Example 1; the porestructure characterization is given in Example 2; the competitivedynamic adsorption procedure and results are provided in Example 3; andthe competitive efficacy for pick up the smaller cyclochrome-c proteinover the larger albumin molecule is discussed under Example 4.

EXAMPLE 1 Adsorbent Syntheses

The synthesis process consists of (1) preparing the aqueous phase, (2)preparing the organic phase, (3) carrying out the suspensionpolymerization, and (4) purifying the resulting porous polymericadsorbent product. The aqueous phase compositions are the same for allthe polymerizations. Table 1A lists the percentage composition of theaqueous phase and Table 1B gives the material charges typical for a five(5) liter-reactor polymerization run.

TABLE 1A Aqueous Phase Composition Wt. % Ultrapure Water 97.787Dispersing Agent: Polyvinylalcohol 0.290 Monosodium Phosphate 0.300Disodium Phosphate 1.000 Trisodium Phosphate 0.620 Sodium Nitrite 0.003

TABLE 1B Material Charges for a Typical Five (5) Liter-ReactorPolymerization Run Volume of Aqueous Phase 1750.00 ml Density of AqueousPhase 1.035 g/ml Weight of Aqueous Phase 1811.25 g Volumetric Ratio,Aqueous Phase/Organic Phase 1.05 Volume of Organic Phase 1665.0 mlDensity of Organic Phase 0.84093 g/ml Weight of Organic Phase, ExcludingInitiator Charge 1400.15 g Total Reaction Volume 3415.0 ml TotalReaction Weight 3211.40 g Initiator, Pure Benzoyl Peroxide (BPO) 8.07606g Initiator, 97% BPO 8.3258 g Commercial 63% Divinylbenzene (DVB)794.814 g [98.65 Polymerizable Monomers of DVB and EVB(Ethylvinylbenzene); 1.35% inert compounds; 63.17% DVB; 35.48% EVB]Toluene 269.300 g Isooctane 336.036 g Benzoyl Peroxide, 97% 8.3258 gTotal, Organic Charge 1408.4758 g (Note: Initiator charge is calculatedon only the quantity of polymerizable monomers introduced into thereactor.)

Upon preparation of the aqueous phase and the organic phase, the aqueousphase is poured into the five-liter reactor and heated to 65° C. withagitation. The pre-mixed organic phase including the initiator is pouredinto the reactor onto the aqueous phase with the stirring speed set atthe rpm for formation of the appropriate droplet size. The dispersion oforganic droplets is heated to the temperature selected for thepolymerization and is held at this temperature for the desired length oftime to complete the conversion of the monomers into the crosslinkedpolymer and, thereby, set the pore structure. Unreacted initiator isdestroyed by heating the bead slurry for two (2) hours at a temperaturewhere the initiator half-life is one hour or less. For the initiator,benzoyl peroxide, the unreacted initiator is destroyed by heating theslurry at 95° C. for two (2) hours.

The slurry is cooled, the mother liquor is siphoned from the beads andthe beads are washed five (5) times with ultrapure water. The beads arefreed of porogen and other organic compounds by a thermal cleaningtechnique. This process results in a clean, dry porous adsorbent in theform of spherical, porous polymer beads.

TABLE 1C Components of Adsorbent Syntheses Adsorbent 1 Adsorbent 3Adsorbent 4 Adsorbent 5 Porous Polymer Identity Wt. %^(a) Adsorbent 2Wt. %^(a) Wt. %^(a) Wt. %^(a) Divinylbenzene, 35.859 Adsorbent 2 26.16322.4127 22.4127 (DVB), Pure is a comercial Ethylvinylbenzene 20.141resin, 14.695 12.5883 12.5883 (EVB), Pure Amberlite Inerts 0.766XAD-16 ®, made 0.559 0.4790 0.4790 Toluene 19.234 by Rohm and 27.26364.521 54.841 Isooctane 24.00 Haas Company 31.319 0.00 9.680Polymerizable 56.00 40.8584 35.00 35.00 Monomers Porogen 44.00 59.141665.00 65.00 Benzoyl Peroxide 1.03 0.7447 2.00 4.00 (BPO), Pure; Wt. %Based Upon Polymerizable Monomer Content Polymerization, 75°/10 hrs80°/16 hrs 70°/24 hrs 65°/24 hrs ° C./time, hrs. 95°/2 hrs  95°/2 hrs ^(a)Wt. % value is based upon the total weight of the organic phaseexcluding the initiator.

EXAMPLE 2 Pore Structure Characterization

The pore structures of the adsorbent polymer beds identified in TABLE 1Cwere analyzed with a Micromeritics ASAP 2010 instrument. The results areprovided in GRAPH 1 where the pore volume is plotted as a function ofthe pore diameter. This graph displays the pore volume distributionacross the range of pore sizes.

The pore volume is divided up into categories within pore size rangesfor each of the five adsorbent polymers and these values are provided inTABLE 2. The Capacity Pore Volume is that pore volume that is accessibleto protein sorption and consists of the pore volume in pores larger than100 Å diameter. The Effective Pore Volume is that pore volume that isselectively accessible to proteins smaller than 35,000 Daltons andconsists of pore diameters within the range of 100 to 250 Å diameter.The Oversized Pore Volume is the pore volume accessible to proteinslarger than 35,000 Daltons and consists of the pore volume in poreslarger than 250 Å diameter. The Undersize Pore Volume is the pore volumein pores smaller than 100 Å diameter and is not accessible to proteinslarger than about 10,000 Daltons.

TABLE 2 Pore Structures of Adsorbents Polymer Adsorber ID Adsorbent 1Adsorbent 2 Adsorbent 3 Adsorbent 4 Adsorbent 5 Capacity Pore Volume,cc/g; Dp, 100 Å 0.5850 1.2450 1.5156 0.3148 0.6854 →2000 Å EffectivePore Volume, cc/g; Dp, 100 Å 0.5678 0.9860 0.3330 0.3060 0.6728 →250 ÅTransport Pore Volume of 0.0172 0.2590 1.1826 0.0088 0.0126 Dp =250~2000 Å, cc/g Effective Pore (100~250 Å)Volume, as 97.06% 79.20%21.97% 97.20% 98.16% % of capacity pore Transport Pore (250-2000 Å)Volume,  2.9%  20.8%  78.0%  2.8%  1.8% as % of capacity pore UndersizedPore Volume, cc/g; Dp < 0.3941 0.5340 0.4068 0.6311 0.4716 100 Å TotalPore Volume, cc/g; Dp, 17 Å 0.9792 1.7790 1.9225 0.9459 1.1569 →2000 ÅPore Vol (cc/g) of Dp = 500 Å to 2,000 Å 0.0066 0.016  0.668  0.00360.0053 Volune of Pores in 100~750 Å, cc/g 0.5816 1.2357 1.4915 0.31330.6825 Volume of Pores in 100~750 Å, as % of  99.4%  99.3%  98.4%  99.5% 99.6% capacity pore Dp = Pore Diameter in Å (Angstrom)

FIG. 1 depicts a Graph of Table 2 showing a plot of pore volume v porediameter (dV/dD vs. D) for Various Adsorbents Measured by NitrogenDesorption Isotherm.

EXAMPLE 3 Protein Adsorption Selectivity

The polymeric adsorbent beads produced in Example 1 are wetted out withan aqueous solution of 20 wt. % isopropyl alcohol and thoroughly washedwith ultrapure water. The beads with diameters within 300 to 850 micronsare packed into a 200 ml hemoperfusion device which is a cylindricalcartridge 5.4 cm in inside diameter and 8.7 cm in length. The beads areretained within the cartridge by screens at each end with an orificesize of 200 microns. End caps with a center luer port are threaded ontoeach end to secure the screens and to provide for fluid distribution andattachment for tubing.

Four liters of an aqueous 0.9% saline solution buffered to a pH of 7.4are prepared with 50 mg/liter of horse heart cytochrome-c and 30 g/literof serum albumin. These concentrations are chosen to simulate a clinicaltreatment of a typical renal patient where albumin is abundant andβ₂-microglobulin is at much lower levels in their blood. Horse heartcytochrome-c with a molecular weight 11,685 daltons has a molecular sizevery close to β₂-microglobulin at 11,845 daltons and, therefore, ischosen as the surrogate for β₂-microglobulin. Serum albumin is a muchlarger molecule than cytochrome-c with a molecular weight of 66,462daltons and, therefore, allows for the appropriate competitiveadsorption studies needed for selecting the porous polymer with theoptimum pore structure for size-selective exclusion of albumin.

The protein solution is circulated by a dialysis pump from a reservoirthrough a flow-through UV spectrophotometer cell, the bead bed, andreturned to the reservoir. The pumping rate is 400 ml/minute for aduration of four (4) hours. The concentration of both proteins in thereservoir is measured periodically by their UV absorbance at 408 nm forcytochrome-c and at 279 nm for albumin.

All five adsorbents identified in TABLE 1C were examined by thiscompetitive protein sorption assessment and the measured results aregiven in TABLE 3.

TABLE 3 Size-Selective Efficacy of Porous Polymeric Adsorbents PolymerAdsorber ID Adsorbent 1 Adsorbent 2 Adsorbent 3 Adsorbent 4 Adsorbent 5Capacity Pore Volume, 0.5850 1.2450 1.5156 0.3148 0.6854 cc/g; Dp, 100Å→2000 Å Effective Pore Volume, 0.5678 0.9860 0.3330 0.3060 0.6728 cc/g;Dp, 100 Å→250 Å Transport Pore Volume of 0.0172 0.2590 1.1826 0.00880.0126 Dp = 250~2000 Å, cc/g Effective Pore 97.06%  79.20%  21.97% 97.20%  98.16%  (100~250 Å)Volume, as % of capacity pore Transport Pore 2.9% 20.8% 78.0%  2.8%  1.8% (250~2000 Å) Volume, as % of capacity poreUndersized Pore Volume, 0.3941 0.5340 0.4068 0.6311 0.4716 cc/g; Dp <100 Å Total Pore Volume, cc/g; 0.9792 1.7790 1.9225 0.9459 1.1569 Dp, 17Å→2000 Å Pore Vol (cc/g) of 0.0066 0.016  0.668  0.0036 0.0053 Dp = 500Å to 2,000 Å Volune of Pores in 0.5816 1.2357 1.4915 0.3133 0.6825100~750 Å, cc/g Volume of Pores in 99.4% 99.3% 98.4% 99.5% 99.6% 100~750Å, as % of capacity pore % Cytochrome-C, 89.0% 96.7% 95.3% 57.4% 90.1%Adsorbed % Albumin Adsorbed  3.7%  8.1%   13%  1.0%  1.8% Selectivity24.05   11.94   7.27  57.1   50.06   Dp = Pore Diameter in Å (Angstrom)

EXAMPLE 4 Pore Volume and Pore Size Range for Suitable Kinetics andSize-Selectivity for Cytochrome-C Over Albumin

TABLE 3 and GRAPH 1 summarize the pertinent pore structure data and theprotein perfusion results carried out on all five (5) adsorbents. Theselectivity for adsorbing cytochrome-c over albumin decreased in thefollowing order: Adsorbent 4>Adsorbent 5>Adsorbent 1>Adsorbent2>Adsorbent 3.

The quantity of cytochrome-c adsorbed during the four hour perfusiondecreased in the following order: Adsorbent 2>Adsorbent 3>Adsorbent5>Adsorbent 1>Adsorbent 4.

Adsorbent 4 with the highest selectivity at 57.1 had the poorestkinetics picking up only 57.4% of the available cytochrome-c over thefour hour perfusion. This kinetic result occurs from the Effective PoreVolume being located at the small end of the pore size range, having allits Effective Pore Volume within the pore size range of 130 to 100 Å.There is insignificant pore volume in pores larger than 130 Å and thissmall pore size retards the ingress of cytochrome-c.

Adsorbent 5 with its major pore volume between 100 to 200 Å had thesecond highest selectivity for cytochrome-c over albumin at 50.6 and ithad good mass transport into the Effective Pore Volume pores picking up90.1% of the cytochrome-c during the four hour perfusion. This porouspolymer has the best balance of properties with excellentsize-selectivity for cytochrome-c over albumin and very good capacityfor cytochrome-c during a four hour perfusion.

Adsorbent 1 showed reasonably good selectivity at 24.05 for sorbingcytochrome-c over albumin. It also exhibited good capacity for sorbingcytochrome-c during the four hour perfusion, picking up 89.0% of thequantity available.

Adsorbent 2 with the highest capacity for sorbing cytochrome-c duringthe four hour perfusion picked up 96.7% of the available cytochrome-c.This high capacity arises from having a large pore volume, 0.986 cc/g,and within the Effective Pore Volume range of 100 Å to 250 Å. However,this porous polymer allowed more albumin to be adsorbed than Adsorbents1, 4, and 5, since it has significant pore volume, 0.250 cc/g, in thepore size group from 250 Å to 300 Å.

Adsorbent 3 with a very broad pore size distribution (see GRAPH 1) hadthe poorest selectivity among the group at 7.27. It has a very largepore volume in the pore size range larger than 250 Å. This porouspolymer has a pore volume of 1.15 cc/g within the pore size range of 250Å to 740 Å. In contrast with the other four adsorbents, this porouspolymer is not size-selective for proteins smaller than about 150,000Daltons, although it did sorb 95.3% of the available cytochrome-c duringthe perfusion.

On balance of properties of selectively for sorbing cytochrome-c overalbumin and its capacity for picking up cytochrome-c during a four hourperfusion, porous polymeric Adsorbent 5, gave the best performance. Thisporous polymer has the proper pore structure to perform well inhemoperfusion in concert with hemodialysis for people with End StageRenal Disease.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the attendant claims attachedhereto, this invention may be practiced other than as specificallydisclosed herein.

What is claimed is:
 1. A hemocompatible size selective polymer systemcomprising at least one polymer formed with at least one crosslinkingagent and in the presence of at one least dispersant, said at least onepolymer defining a porous structure wherein said porous structureconsists of a plurality of pores with diameters in the range of 17Angstroms to about 2000 Angstroms, said at least one polymer comprisingtransport pores with diameters from about 250 Angstroms to about 2000Angstroms and effective pores with diameters greater than 100 Angstromsto about 250 Angstroms, said at least one polymer having a transportpore volume greater than about 1.8 to about 78% of a capacity porevolume of said at least one polymer and an effective pore volume greaterthan about 22 to less than about 98.2% of the capacity pore volume. 2.The system of claim 1 wherein said at least one crosslinking agent isselected from a group consisting of divinylbenzene, trivinylbenzene,divinylnaphthalene, trivinylcyclohexane, divinylsulfone,trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate,trimethylolpropane triacrylate, trimethylolpropane diacrylate,pentaerythritol dimethacrylate, pentaerythritol trimethacrylate,pentaerythritol tetramethacrylate, pentaerythritol diacrylate,pentaerythritol triacrylate pentaerythritol tetraacrylate,dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate,dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate,dipentaerythritol triacrylate, dipentaerythritol tetraacrylate,divinylformamide and mixtures thereof.
 3. The system of claim 1 whereinsaid at least one dispersant is selected from a group consisting ofalbumin, carrageenan, konjac flour, guar gum, xanthan gum, gum Arabic,gum tragcanth, locust bean gum, karaya gum, salts ofcarboxymethylcellulose, salts of carboxyethylcellulose, salts ofhyaluronic acid, salts of poly(maleic acid), salts of poly(itaconicacid), Type B gelatin, poly(acrylamide), poly(methacrylamide), salts ofpoly(acrylamide-co-acrylic acid), salts ofpoly(acrylamide-co-methacrylic acid), salts ofpoly(methacrylamide-co-acrylic acid), salts ofpoly(methacrylamide-co-methacrylic acid), hydroxyethyl cellulose,hydroxypropyl cellulose, poly(hydroxyethyl methacrylate),poly(hydroxypropyl acrylate), poly(dimethylaminoethyl methacrylate),poly(dimethylaminoethyl acrylate), poly(dimethylaminoethylmethacrylate), poly(diethylaminoethyl acrylate), poly(vinyl alcohol),poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and saltsof poly(acrylic acid) and mixtures thereof.
 4. The system of claim 1wherein the presence of said at least one dispersant forms ahemocompatible surface on said at least one polymer.
 5. The system ofclaim 1 wherein said at least one polymer is used in direct contact withwhole blood to sorb protein molecules selected from a group consistingessentially of cytokines and 82-microglobulin and exclude the sorptionof large blood proteins, said large blood proteins being selected from agroup consisting essentially of hemoglobin, albumin, immunoglobulins,fibinogen, serum proteins and other blood proteins larger than 50,000Daltons.
 6. The system of claim 1 wherein said at least one polymer hasan internal surface selectivity for absorbing proteins being smallerthan 50,000 Daltons, having little to no selectivity for adsorbingvitamins, glucose, electrolytes, fats, and other hydrophilic smallmolecular nutrients carried by the blood.
 7. The system of claim 1wherein said at least one polymer is made using suspensionpolymerization.
 8. The system of claim 1 wherein said at least onepolymer is formed by polymerizing monomers in the presence of at leastone free radical inhibitor and at least one buffering agent.
 9. A sizeselective hemocompatible surface coated polymer system comprising atleast one polymer formed by polymerizing monomers in an organic phase,said organic phase comprises polymerizable monomers and at least oneinitiator and wherein said organic phase is dispersed in an aqueousphase, said aqueous phase comprises at least one dispersing agent, atleast one free radical inhibitor and at least one buffering agent, saidat least one polymer defining a porous structure wherein said porousstructure consists of a plurality of pores with diameters in the rangeof 17 Angstroms to about 2000 Angstroms, said at least one polymercomprising transport pores with diameters from about 250 Angstroms toabout 2000 Angstroms and effective pores with diameters greater than 100Angstroms to about 250 Angstroms, said at least one polymer having atransport pore volume greater than about 1.8 to about 78% of a capacitypore volume of said at least one polymer and an effective pore volumegreater than about 22 to less than about 98.2% of the capacity porevolume.
 10. The system of claim 9 wherein said polymerizable monomersare monofunctional monomers, said monofunctional monomers are selectedfrom a group consisting of styrene and ethylvinylbenzene, and saidsystem further comprises at least one crosslinking agent selected from agroup consisting essentially of divinylbenzene, trivinylcyclohexane,trivinylbenzene, divinylnaphthalene, divinylsulfone, trimethylolpropanetriacrylate, trimethylolpropane trimethacrylate and mixtures thereof.11. The system of claim 9 further comprising at least one crosslinkingagent is selected from a group consisting of divinylbenzene,trivinylbenzene, divinylnaphthalene, trivinylcyclohexane,divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropanedimethacrylate, trimethylolpropane triacrylate, trimethylolpropanediacrylate, pentaerythritol dimethacrylate, pentaerythritoltrimethacrylate, pentaerythritol tetramethacrylate, pentaerythritoldiacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate,dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate,dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate,dipentaerythritol triacrylate, dipentaerythritol tetraacrylate,divinylformamide and mixtures thereof.
 12. The system of claim 9 whereinsaid at least one initiator is selected from a group consisting ofdiacylperoxides, ketone peroxides, peroxyesters, dialkyl peroxides,peroxyketals, azoalkylnitriles, peroxydicarbonates and mixtures thereof.13. The system of claim 9 wherein said at least one dispersant isselected from a group consisting of albumin, carrageenan, konjac flour,guar gum xanthan gum, gum Arabic, gum tragcanth, locust bean gum, karayagum, salts of carboxymethylcellulose, salts of carboxyethylcellulose,salts of hyaluronic acid, salts of poly(maleic acid), salts ofpoly(itaconic acid), Type B gelatin, poly(acrylamide),poly(methacrylamide), salts of poly(acrylamide-co-acrylic acid), saltsof poly(acrylamide-co-methacrylic acid), salts ofpoly(methacrylamide-co-acrylic acid), salts ofpoly(methacrylamide-co-methacrylic acid), hydroxyethyl cellulose,hydroxypropyl cellulose, poly(hydroxyethyl methacrylate),poly(hydroxypropyl acrylate), poly(dimethylaminoethyl methacrylate),poly(dimethylaminoethyl acrylate), poly(dimethylaminoethylmethacrylate), poly(diethylaminoethyl acrylate), poly(vinyl alcohol),poly(N-vinylpyrrolidinone), salts of poly(methacrylic acid), and saltsof poly(acrylic acid) and mixtures thereof.
 14. The system of claim 9wherein said at least one free radical inhibitor is selected from agroup consisting of p-nitrosophenoxide salts, sodium nitrate,N-hydroxy-N-methylglucamine, N-nitroso-N-methylglucamine and mixturesthereof.
 15. The system of claim 9 wherein said at least one bufferingagent is selected from a group consisting of carbonate salts,bicarbonate salts, boric acid salts, salts of phosphoric acid andmixtures thereof.
 16. The system of claim 9 wherein said organic phasefurther comprises at least one porogen, said at least one porogen beingselected from a group consisting of aliphatic hydrocarbons, dialkylketones, aliphatic carbinols and mixtures thereof.
 17. A hemocompatiblesize selective polymer system comprising at least one polymer formed bypolymerizing monomers in an organic phase dispersed in an aqueous phase,said organic phase comprises polymerizable monomers and at least oneinitiator and wherein said organic phase is dispersed in an aqueousphase, said aqueous phase comprises at least one dispersing agent, atleast one free radical inhibitor and at least one buffering agent, saidat least one polymer defining a porous structure, said porous structureconsisting of pores with diameters in the range of 17 Angstroms to about2000 Angstroms, said at least one polymer comprising transport poreswith diameters from about 250 Angstroms to about 2000 Angstroms andeffective pores with diameters greater than 100 Angstroms to about 250Angstroms, said at least one polymer having a transport pore volumegreater than about 1.8 to about 78% of a capacity pore volume of said atleast one polymer and an effective pore volume greater than about 22 toless than about 98.2% of the capacity pore volume.
 18. The system ofclaim 17 wherein said polymerizable monomers are monofunctionalmonomers, said monofunctional monomers are selected from a groupconsisting of styrene and ethylvinylbenzene, and said system furthercomprises at least one crosslinking agent selected from a groupconsisting essentially of divinylbenzene trivinylcyclohexane,trivinylbenzene, divinylnaphthalene, divinylsulfone, trimethylolpropanetriacrylate, trimethylolpropane trimethacrylate and mixtures thereof.19. The system of claim 17 wherein said at least one initiator isselected from a group consisting of diacylperoxides, ketone peroxides,peroxyesters, dialkyl peroxides, peroxyketals, azoalkylnitriles,peroxydicarbonates and mixtures thereof.